Abstract
AbstractWhile sclerostin-neutralizing antibodies (Scl-Ab) transiently stimulate bone formation by activating Wnt signaling in osteoblast lineage cells, they exert sustained inhibition of bone resorption, suggesting an alternate signaling pathway by which Scl-Ab control osteoclast activity. Since sclerostin can activate platelet-derived growth factor receptors (PDGFRs) in osteoblast lineage cellsin vitroand PDGFR signaling in these cells induces bone resorption through M-CSF secretion, we hypothesized that the prolonged anti-catabolic effect of Scl-Ab could result from PDGFR inhibition. We show here that inhibition of PDGFR signaling in osteoblast lineage cells is sufficient and necessary to mediate prolonged Scl-Ab effect onCsf1expression (encoding M-CSF) and osteoclast activity in mice. Indeed, sclerostin co-activates PDGFRs independently of Wnt/β-catenin signaling inhibition, by forming a ternary complex with LRP6 and PDGFRs. In turn, Scl-Ab prevents sclerostin-mediated co-activation of PDGFR signaling and consequentCsf1up-regulation in osteoblast cultures, thereby inhibiting bone resorption in osteoblasts/osteoclasts co-cultures. These results provide a new potential mechanism explaining the lack of counter-regulation of Scl-Ab effect on bone resorption.
Publisher
Cold Spring Harbor Laboratory